Pharmacokinetic interaction between tandospirone and fluvoxamine in the rat contextual conditioned fear stress model and its functional consequence: Involvement of cytochrome P450 3A4.
OBJECTIVE
In a previous study it was demonstrated that the anxiolytic action of tandospirone, a 5-hydroxytryptamine (5-HT)(1A) receptor agonist, is facilitated by cytochrome P450 (CYP) 3A4 inhibitors, such as ketoconazole and cimetidine. It is also known that fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI), inhibits CYP3A4. The purpose of the present study was to clarify the pharmacokinetic interaction between tandospirone and fluvoxamine and to evaluate their combined effect in the rat anxiety model.


METHODS
The anxiolytic action of co-administration of tandospirone and fluvoxamine was examined using the rat contextual conditioned fear stress model. After testing the conditioned fear, plasma concentrations of tandospirone and its major metabolite 1-(2-pyrimidyl) piperazine were determined.


RESULTS
One day after fear conditioning, both tandospirone (60 mg/kg, p.o.) and fluvoxamine (60 mg/kg, p.o.) significantly inhibited conditioned freezing and their combination effect was additive. In addition, plasma concentration of tandospirone was increased by fluvoxamine.


CONCLUSIONS
There is a CYP3A4-related drug-drug interaction between tandospirone and fluvoxamine. Therefore, fluvoxamine may facilitate the anxiolytic effect of tandospirone via CYP3A4 inhibition.
Nishikawa
Hiroyuki
H
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan. hnishika@med.hokudai.ac.jp
Inoue
Takeshi
T
Masui
Takuya
T
Izumi
Takeshi
T
Nakagawa
Shin
S
Koyama
Tsukasa
T
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004357:Drug Synergism; D004597:Electroshock; D005239:Fear / Q000187:drug effects*; D016666:Fluvoxamine / Q000493:pharmacokinetics* / Q000494:pharmacology; D054833:Isoindoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D014151:Anti-Anxiety Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; C055267:tandospirone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016666:Fluvoxamine